As a continuing effort to develop small molecules useful as immune modulators, we will screen large small molecule libraries in NIH in collaboration with the MLPCN screening center in University of New Mexico. Upon completion of the HTS campaign, we will commence hit validation process in pursuit of lead compounds. Once leads are identified, we will investigate the mechanisms underlying the inhibition by those leads of TCRplus LFA-1-mediated 2C T cell absorption of nanometric vesicles at the molecular level and pursue lead optimization. In addition, we will continue to explore molecular mechanisms for the inhibition of the vesicle absorption by the mitochondrial antagonists. Specifically, we will focus our efforts on documenting the role of AMPK in the control of TCR-proximal signaling for LFA-1 activation and identifying target(s) of AMPK intimately associated with the control mechanism. We will also explore the mechanism underlying the promotion of the pMV absorption by the molecules used as antidepressants by carrying out extended SAR study and investigating their target protein(s) in T cells.